Paraquat, an herbicide, has caused over 400 accidental human deaths. Its principal site of toxicity is the lung but its molecular mechanism of action is unknown and no adequate therapy is available. We propose that sites discovered by us to be poisoned in cells by hyperbaric oxygen, are also poisoned by paraquat since evidence indicates that oxygen radicals are involved in both toxicities. Consequently, we predict that compounds which we find protective for oxygen toxicity, will be therapeutic for paraquat poisoning. Specifically, we postulate that paraquat will poison six enzymes required for synthesis of ten amino acids, and quinolinate phosphoribosyltransferase (QPT) which is necessary for pyridine nucleotide coenzyme (PNC) synthesis. In medium deficient in the amino acids, the stringent genetic response should be induced by paraquat, and lead to indirect inhibition of the many metabolic processes known to be regulated by guanine tetraphosphate (ppGpp), the product of stringency. To evaluate these theories, stringent and relaxed strains of Escherichia coli animal primary cell suspensions, and laboratory rats will be used. The mammalian systems will be used only for the PNC mechanism studies since they do not undergo stringency. ppGpp will be detected by autoradiography and quantified by scintillation spectrometry after thin-layer chromotography with bacteria grown with (14C)-guanine. The predicted inhibitions by paraquat and the protective effects of niacin (for PNC synthesis), thiamine, and of specific amino acids will be measured in bacteria, tissue suspensions, and rats by plate colony counts, biochemical analyses, and survival studies. PNC will be measured by a sensitive recycling technique and individual enzymes will be measured by spectrophotometric and 14C-assays. Reasons for the unique sensitivity of particular enzymes to paraquat will be sought at the structural level. The potential role and mechanism of niacin and thiamine for protection against poisoning of rat lung by paraquat will be assessed by determining survival, lung pathology and concentrations of PNC, niacin, thiamine, and QPT in tissues.